Erlotinib is a drug used in the treatment of cancer diseases, in particular for lung and pancreatic cancer. Erlotinib is an inhibitor of the tyrosine kinase receptor, acting in particular by inhibiting the EGF receptor, the epidermal growth factor receptor; in cancer there is the over-expression of growth factor receptors and related ligands. These are, in fact, some of the factors involved in processes of cancer etiopathogenesis. The stimulation of the growth factors leads to an increase of the cell proliferation with the consequent starting of the disease. The receptors, once bound the ligand, self-phosphorylate so generating a cascade of intracellular reactions that lead to the activation of transcription factors involved in the cell proliferation. Erlotinib binds itself to the intracellular catalytic portion of the receptor miming the ATP structure, but being more stable than that, they bind to the receptor and inhibit it. Therefore the activation of the cell reactions is not allowed, so blocking the cell expansion.
Erlotinib is a compound of formula (I)
chemically known as N-3-(ethynyl-phenyl)-6,7-bis-(2-methoxyethoxy)-4-quinazolin amine, described in WO 96/30347 and marketed with the trademark Tarceva®.
WO 96/30347 describes a process for the synthesis of Erlotinib reported in the following scheme 1:

EP 1 044 969 describes a process for the synthesis of Erlotinib reported in the following scheme 2:

U.S. Pat. No. 7,960,545 discloses a process for the synthesis of Erlotinib reported in the following scheme 3:

EP 2 433 934 describes a process for the synthesis of Erlotinib reported in the following scheme 4:

All these processes foresee numerous steps for the preparation of the key intermediate, 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline, that is then reacted with 3-ethynylaniline or a derivative thereof.
WO 2007/138612 and WO 2007/138613 describe a process for the synthesis of Erlotinib reported in the following scheme 5:

The processes described in WO 07/138612 and WO 07/138613 have the advantage to reduce the number of steps avoiding the formation and the isolation of the intermediate 4-chloro-6,7-bis(2-methoxyethoxy)quinazoline but they necessarily require the formation and the isolation of the intermediate obtained by the reaction with N,N-dimethylformamide dimethylacetal.
We have now found that it is possible to further reduce the number of synthetic steps, the use of expensive reagents and the isolation of intermediates so obtaining Erlotinib through a simpler and cheaper process.